Tyrosine kinase is an enzyme which phosphorylates tyrosine residues in substrate proteins, and is known to play an important role in an intracellular signal transduction system concerning cellular differentiation and proliferation. Especially, it is known that a growth factor receptor tyrosine kinase (hereinafter receptor tyrosine kinase) such as HER2 (also called as ErbB2 or Neu) and EGF receptor etc. are considerably involved in cancer development, and their activities are increased in a variety of human cancers (Non-Patent Literature 1, Non-Patent Literature 2 and Non-Patent Literature 3).
Also it is known that co-expression of EGF receptor and HER2 further promotes canceration by EGF receptor alone (Non-Patent Literature 4) and a dual inhibitor that inhibits tyrosine kinase of both EGF receptor and HER2 is advantageous in having superior therapeutic effect in wider range of disease by synergistic effect of dual inhibition when compared with a EGF receptor or a HER2 selective inhibitor.
A quinazoline derivative (VI) having a substituent containing an alkoxyimino structure at 6-position:
wherein R2 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or formula: —Y—Ry wherein Y is —O—, —S—, —SO2— or alkylene which may be intervened with —O—, —S— or —N(Rz)—; and Ry is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Rz is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl or substituted or unsubstituted aralkyloxycarbonyl;R3 and R4 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy, mercapto, cyano or substituted or unsubstituted amino;R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl or substituted or unsubstituted amino, andR6 is substituted or unsubstituted C1-3 alkylene,is one of these dual inhibitors and is expected as a novel cancer agent (Patent Literature 1).
A compound (III) having a 1-oxo-2-butyn-1-yl substituent at 6-position:
wherein R2, R3 and R4 are as defined above,is an important synthetic intermediate for preparing a quinazoline derivative (VI), since the above quinazoline derivative (VI) is prepared by reacting a compound (III) with an alkoxyamine derivative.
In addition, Patent Document 2 discloses that a process for producing a compound represented by Formula (III):
wherein R2 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or a group represented by the formula: —Y—Ry wherein —Y— is —O—, —S—, —SO2— or alkylene which may be intervented with —O—, —S— or —N(RZ)—; and Ry is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; RZ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, etc.; R3 and R4 are each independently hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, etc.;characterized in thatReaction A, in which a compound represented by the formula (I):
wherein R1 is a group represented by the formula: —O—RX or —S—RX wherein RX is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl etc., R2, R3 and R4 are as defined above,is reacted with a compound represented by the formula: (RbO—)N(—Ra)Hwherein Ra and Rb are each independently substituted or unsubstituted C1-C3 alkyl, and one or more metallic reagent(s) selected from the group consisting of Grignard reagent, sodium hydride, alkyllithium, alkenyllithium, alkynyllithium, phenyllithium, and lithium amide;and Reaction B, in which the product of Reaction A is reacted with 1-propynyl metal acetylide;are carried out substantially as one step by continuously conducting these two reactions.
Non-patent Documents 5-9 disclose Sonogashira-carbonylation reactions using liquid alkyne, but Sonogashira-carbonylation reaction using gaseous alkyne (example: acetylene, propyne) has not been known.
Non-patent Document 10 discloses that N,N-dimethylglycine is effective as ligand for copper, but it has not been reported that the ligand is involved in the precipitate of the palladium metal. Neither are there any examples of adding an effective ligand (additive) for copper to control the precipitate of palladium metal in various Sonogashira reactions in Non-patent Document 11.
Sonogashira-carbonylation reactions by using iodobenzene, carbon monoxide, phenylacetylene, triethylamine and palladium catalyst are described in Non-patent Document 12. Example of the reaction in which triethylamine hydroiodide salt is generated as by-product is disclosed, but new compound and the crystal thereof of the present invention are not disclosed.